The present invention discloses in vivo methods that are useful, for example, for exciting individual cells without piercing them, for diagnostic applications like peripheral nerve conduction studies, evoking potentials and mapping neurological functions. The method is also useful for removing electrical artifacts that are commonly found when electrical stimulation is used. Finally, the method is useful for stimulating small subunits of nerve fibers.
Various methods may be used to stimulate neural tissue. Several of the traditional methods of stimulation include electrical, mechanical, thermal, and chemical. A neuron will propagate an electrical impulse after applying a stimulus. The most common form of applying such stimulus is to form a transient current or voltage pulse applied through electrodes. Electrical stimulation, as well as mechanical and chemical stimulation, has many limitations. To name a few, stimulation by such methods may result in non-specific stimulation of neurons or damage to neurons. Difficulty exists in recording electrical activity from the neuron due to an electrical artifact created by the stimulus. To stimulate only one or a few neurons, fragile micro-electrodes need to be fashioned and carefully inserted into the tissue to be stimulated. Such techniques do not easily lend themselves to implantable electrodes used for long term stimulation of neural tissue.
Fork was the first to report a direct stimulation of nerve fibers using low-energy laser light (Fork, R., “Laser stimulation of nerve cells in Aplysia”, Science, March(5): p. 907-8, 1971.) Laser irradiation at (488 nm, 515 nm, and 1006 nm) was applied to the abdominal ganglion of Aplysia Californica that possesses some light sensitive properties. The author observed that the cells fired when the light at 488 nm was turned on in some cases and turned off in others. In another study, bundles of rat nervous fibers were stimulated using a XeCl laser (Allegre, G., S. Avrillier, and D. Albe-Fessard, “Stimulation in the rat of a nerve fiber bundle by a short UV pulse from an excimer laser”, Neuroscience Letters, 180(2): p. 261-4, 1994.) When stimulated using a laser pulse transmitted through an optical fiber, a response similar to that obtained with electrical stimulation was observed. A threshold stimulation level of 0.9 J/cm2 was reported for optical stimulation. No other reports by the same authors have been published since. Thus, optical energy can be used to stimulate nerve fibers. Although there is ample evidence that photon energy effects neural tissue in humans and animals, a need remains for a method that can be used to stimulate neural tissue without damaging such tissue or producing artifacts. Furthermore, in order for such an invention to be useful in both research and clinical applications, it should produce activity in neurons by delivery of energy without the addition of potentially toxic dyes or at intensities destructive to the neuron over useful periods of time. Finally, there is a need for a method of precisely stimulating an individual neuron with optical energy without piercing tissue.
One common way of providing light energy for stimulation of neural tissues is by using a laser. Lasers are characterized by their wavelength and energy level. Classically, lasers have been used in biological applications for tissue ablation. However, low power lasers are available for uses other than tissue ablation. The energy required for stimulation large populations of neurons is very small, and the energy required to stimulate an individual neuron is exceedingly small. Manipulation of strength, duration and frequency of stimulation are key parameters that determine whether a neuron will fire. Such parameters are adjustable with pulsed, optical energy and can be adjusted to a range acceptable for stimulation of neural tissue. Additionally, the precision of laser energy delivery can easily provide a novel method of selectively stimulating individual neurons or different nerve fibers within a large population of neurons without the need to pierce tissue.
It is clear that several major drawbacks exist with respect to the current stimulation methods that are available. Thus, a method of optical stimulation for neural tissue is needed.
The present invention provides methods for stimulating neural tissue with optical energy. Although the present invention is not bound by mechanism or theory, it is related to the surprising discovery by the inventors of methods of stimulating neural tissue with optical energy. Stimulation of neural tissue in this regard includes, but is not limited to, generation and propagation of an electrical impulse in one or more neurons after applying an optical stimulus. In addition, there is a unique basic science and clinical need for producing an artifact-free response in neurons that causes no damage to the tissue.
One advantage of the present invention is that the methods of stimulating neural tissue described herein are contemplated to be highly specific to individual nerve fibers As intensity of electrical stimulation increases, progressively greater numbers of neurons are activated. This is a physical property of associated with increasing the electrical field size. Optical energy, however, can be confined to a predetermined, physical “spot” size, which is independent of the energy delivered. This physical property is what allows optical techniques to be unique in stimulation of individual or selected neurons. Another advantage of the present invention is the use of the methods of stimulation of neural tissues in vivo. In vitro methods of stimulation, on the other hand, do not lend themselves to the uses of an in vivo method.
Still another advantage of the present invention is that optical stimulation of neural tissue is not associated with an electrical stimulus artifact. Thus, when optically stimulating individual or multiple neurons stimulated by optical energy, electrical stimulus artifacts are not present.
Still another advantage of this method is that the use of low energy laser stimulation provides precise localization without tissue contact, resulting in high specificity. Such specificity is of use clinically when nerve stimulation is used for diagnostic applications like identification of subsets of peripheral nerve fibers during operative repair of severed nerves. Also, such technology would allow multiple, focused laser stimuli, to be used to provide functional mapping of neural networks and their interconnections. This advantage may also be applied in therapeutic situations such as neural modulation for pain management, control of movement disorders, and seizure reduction.
Additional aspects, embodiments, and elements of the present invention are described below, including the detailed description of the invention, the examples, and the claims. Aspects, embodiments, and elements described herein are not meant to limit the present invention in any way. Further aspects, embodiments, elements and equivalents thereof, will be readily apparent based upon the present disclosure and are considered to be within the spirit and scope of the present invention.